(1) Field of the Invention:
This invention relates to an improvement in an aqueous solution which contains a lipid-soluble pharmaceutical substance, namely, a lipid-soluble active vitamin substance and/or ubiquinone.
By the term "lipid-soluble active vitamin substance" is meant one or more substances selected from the group consisting of lipid-soluble sources of vitamin A , lipid-soluble sources of vitamin E and lipid-soluble sources of vitamin K.
(2) Description of the Prior Art:
Vitamin A has been known as a substance important for the promotion of growth, visual function and reproduction. It is recently attracting attention for its reported carcinostatic activities. On the other hand, vitamin E and vitamin K have been finding wide-spread clinical utility respectively owing to the biochemical anti-oxidation and biomembrane stabilization effects and as a substance pertaining to blood clotting and the electron transport system. These vitamins are these days desired to be available as aqueous solutions.
On the other hand, the term "ubiquinone" as used herein may embrace a variety of substances which individually contain different numbers of isoprene moieties in their structures. All of these ubiquinone substances have already been found effective substances in view of their physiological activities or effects such as supply of energy for cell activities, anti-oxidation effects, immune reinforcement reaction and aldosterone antagonism. Among such ubiquinone substances, a ubiquinone substance which is generally called ubidecarenone or CoQ.sub.10 and contains 10 isoprene moieties has been formed into pharmaceutical preparations.
Reflecting on finding of such pharmaceutical substances which are applicable in a yet broader field in recent years, a new desire has arisen for the availability of such pharmaceutical substances as aqueous solutions rather than as solid forms.
As a method for solubilizing the above-mentioned lipidsoluble active vitamin substance and or ubiquinone, there is a conventional technique which makes use of a non-ionic surfactant, for example, HCO-60 (trade name; product of Nikko Chemical Co., Ltd., Japan). This prior art method however requires a great deal of HCO-60. As a result, the thus-prepared aqueous solution is susceptible of liberating histamine-like substances due to HCO-60 when administered as an injectable preparation, or when administered as an orally-dosable preparation, creates problems in the intestinal tract and thus brings about undesirable side effects such as diarrhea.
It has also been known to employ lecithin as an emulsifier. However, lecithin has weak emulsification capacity only. Therefore, this method requires a special apparatus called "pressure homogenizer". Moreover, the long-term stability of each resulting emulsion is not considered to be sufficient, thereby requiring such an additive as vegetable oil or ethanol (see, Japanese Patent Application Laid-open No. 56315/1978).
Accordingly, the present inventors developed techniques both featuring an incorporation of a hydrogenated lecithin with a view toward providing an aqueous solution which contains a lipid-soluble active vitamin substance and/or ubiquinone and remains stable over a prolonged period of time without need for the addition of any additive causing potential problems (see, Japanese Patent Application Nos. 209972/1981 and 212695/1982).
Thereafter, the present inventors made a further investigation on such aqueous solutions, resulting in the finding that it is preferable to adjust the pH of such an aqueous solution to 5.5-8. Since the aqueous solution is primarily used as an injectable preparation or orally-dosable preparation for pharmaceutical applications, it is desired to adjust its pH to the physiological pH range of living bodies, namely, to 5.5-8. Thus, additives were freely chosen to adjust the pH level of the above-mentioned aqueous solution. Such additives were incorporated to obtain final products. As a result, the resultant aqueous solutions tended to show some turbidity on visual inspection. When they were subjected to sterilization under suitable conditions, a significant clarity change was observed after the sterilization. Hence, it became necessary to make a search for an additive capable of adjusting the pH to 5.5-8 without developing any significant turbidity by such an adjustment, and a variety of substances were studied, leading to completion of the present invention.